Rare CACNA1A mutations leading to congenital ataxia.
26 May 2020-Pflügers Archiv: European Journal of Physiology (Springer Berlin Heidelberg)-Vol. 472, Iss: 7, pp 791-809
TL;DR: The report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration are dealt with.
Abstract: Human mutations in the CACNA1A gene that encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 (P/Q-type) Ca2+ channel cause multiple neurological disorders including sporadic and familial hemiplegic migraine, as well as cerebellar pathologies such as episodic ataxia, progressive ataxia, and early-onset cerebellar syndrome consistent with the definition of congenital ataxia (CA), with presentation before the age of 2 years. Such a pathological role is in accordance with the physiological relevance of CaV2.1 in neuronal tissue, especially in the cerebellum. This review deals with the report of the main clinical features defining CA, along with the presentation of an increasing number of CACNA1A genetic variants linked to this severe cerebellar disorder in the context of Ca2+ homeostasis alteration. Moreover, the review describes each pathological mutation according to structural location and known molecular and cellular functional effects in both heterologous expression systems and animal models. In view of this information in correlation with the clinical phenotype, we take into consideration different pathomechanisms underlying the observed motor dysfunction in CA patients carrying CACNA1A mutations. Present therapeutic management in CA and options for the development of future personalized treatment based on CaV2.1 dysfunction are also discussed.
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TL;DR: In this paper, a case of late-onset ataxia type 2 was associated with the first multiple base pair insertion in CACNA1A, suggesting that genetically induced reduction in calcium channel function may associate with cases of lateonset EA2.
Abstract: Episodic ataxia type 2 (EA2) is caused by calcium channel (CACNA1A) mutations and typically begins before age 20 years. The molecular basis of late-onset EA2 is unclear. The authors describe a case of late-onset EA2 associated with the first multiple–base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2.
37 citations
TL;DR: In this article, a review summarizes the current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels, with a special focus on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts.
Abstract: This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.
26 citations
TL;DR: In this paper, a comprehensive review of the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels was presented, which indicated that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain.
Abstract: Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl- channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability.
11 citations
TL;DR: The first patients harboring homozygous disease-related variants in three genes were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively as discussed by the authors.
Abstract: A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.
10 citations
References
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TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
1,558 citations
"Rare CACNA1A mutations leading to c..." refers background in this paper
...This applies to SCA6-associated mutations [94, 135, 147] and most EA2linked genetic variants [25, 58, 59, 94, 97, 101, 102, 108, 110, 129, 133, 134]....
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TL;DR: Through its unique selectivity for some cyclin-dependent kinases, roscovitine provides a useful antimitotic reagent for cell cycle studies and may prove interesting to control cells with deregulated cdc2, cdk2 or cdk5 kinase activities.
Abstract: Cyclin-dependent kinases (cdk) play an essential role in the intracellular control of the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. Enzymatic screening has recently led to the discovery of specific inhibitors of cyclin-dependent kinases, such as butyrolactone I, flavopiridol and the purine olomoucine. Among a series of C2, N6, N9-substituted adenines tested on purified cdc2/cyclin B, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine) displays high efficiency and high selectivity towards some cyclin-dependent kinases. The kinase specificity of roscovitine was investigated with 25 highly purified kinases (including protein kinase A, G and C isoforms, myosin light-chain kinase, casein kinase 2, insulin receptor tyrosine kinase, c-src, v-abl). Most kinases are not significantly inhibited by roscovitine. cdc2/cyclin B, cdk2/cyclin A, cdk2/cyclin E and cdk5/p35 only are substantially inhibited (IC50 values of 0.65, 0.7, 0.7 and 0.2 microM, respectively). cdk4/cyclin D1 and cdk6/cyclin D2 are very poorly inhibited by roscovitine (IC50 > 100 microM). Extracellular regulated kinases erk1 and erk2 are inhibited with an IC50 of 34 microM and 14 microM, respectively. Roscovitine reversibly arrests starfish oocytes and sea urchin embryos in late prophase. Roscovitine inhibits in vitro M-phase-promoting factor activity and in vitro DNA synthesis in Xenopus egg extracts. It blocks progesterone-induced oocyte maturation of Xenopus oocytes and in vivo phosphorylation of the elongation factor eEF-1. Roscovitine inhibits the proliferation of mammalian cell lines with an average IC50 of 16 microM. In the presence of roscovitine L1210 cells arrest in G1 and accumulate in G2. In vivo phosphorylation of vimentin on Ser55 by cdc2/cyclin B is inhibited by roscovitine. Through its unique selectivity for some cyclin-dependent kinases, roscovitine provides a useful antimitotic reagent for cell cycle studies and may prove interesting to control cells with deregulated cdc2, cdk2 or cdk5 kinase activities.
1,340 citations
"Rare CACNA1A mutations leading to c..." refers background in this paper
...In this respect, derivatives of roscovitine, a cyclin-dependent kinase (Cdk) inhibitor [80] also displaying agonist action on CaV channels [12, 23, 142], appear to be effective activators of CaV2 channels (including CaV2....
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TL;DR: The molecular relationships and physiological functions of these voltage-gated Ca(2+) channel proteins are presented and information on their molecular, genetic, physiological, and pharmacological properties is provided.
Abstract: Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.
1,295 citations
"Rare CACNA1A mutations leading to c..." refers background in this paper
...The N- and C-termini along with the intracellular loops between α1A homologous domains serve as a platform for channel gating regulation throughmultiple intracellular signaling pathways, including presynaptic proteins [8, 21, 29, 64, 102, 103, 146] and Ca influx through the channel in a calmodulindependent manner [19, 21, 24, 73, 104]....
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...1 channels are located at presynaptic terminals [137] in close coupling to the release of neurotransmitters [21]....
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TL;DR: This crystal structure of a voltage-gated Na+ channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level.
Abstract: Voltage-gated sodium (NaV) channels initiate electrical signalling in excitable cells and are the molecular targets for drugs and disease mutations, but the structural basis for their voltage-dependent activation, ion selectivity and drug block is unknown. Here we report the crystal structure of a voltage-gated Na+ channel from Arcobacter butzleri (NavAb) captured in a closed-pore conformation with four activated voltage sensors at 2.7 A resolution. The arginine gating charges make multiple hydrophilic interactions within the voltage sensor, including unanticipated hydrogen bonds to the protein backbone. Comparisons to previous open-pore potassium channel structures indicate that the voltage-sensor domains and the S4–S5 linkers dilate the central pore by pivoting together around a hinge at the base of the pore module. The NavAb selectivity filter is short, ∼4.6 A wide, and water filled, with four acidic side chains surrounding the narrowest part of the ion conduction pathway. This unique structure presents a high-field-strength anionic coordination site, which confers Na+ selectivity through partial dehydration via direct interaction with glutamate side chains. Fenestrations in the sides of the pore module are unexpectedly penetrated by fatty acyl chains that extend into the central cavity, and these portals are large enough for the entry of small, hydrophobic pore-blocking drugs. This structure provides the template for understanding electrical signalling in excitable cells and the actions of drugs used for pain, epilepsy and cardiac arrhythmia at the atomic level. The X-ray crystal structure of a voltage-gated sodium channel from Arcobacter butzleri has been determined, with the channel in the closed-pore conformation. Channels of this type initiate electrical signalling in excitable cells and are the molecular targets for many drugs, but the structural basis for their voltage-dependent activation and ion selectivity is not known. The selectivity filter in this sodium channel is found to be quite short, compared with those in open-pore potassium channels, and the voltage-sensor domains and linkers between segments S4 and S5 seem to dilate the central pore by pivoting together.
1,273 citations
"Rare CACNA1A mutations leading to c..." refers background in this paper
...In particular, conserved negative, polar, and hydrophobic residues on the S2 helices and an invariant aspartate residue on the S3 segments are necessary contributors to the energy pathway for S4 gating charge movement [16, 20, 51, 93, 113]....
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TL;DR: This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.
Abstract: Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.
976 citations